JP2022065088A - Diagnosis of immune activation using clever-1, tnf-alpha, and hla-dr binding agents - Google Patents
Diagnosis of immune activation using clever-1, tnf-alpha, and hla-dr binding agents Download PDFInfo
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Abstract
Description
本発明は、免疫活性化における使用のためのCLEVER-1に結合することのできる薬剤およびそれに基づく方法に関する。 The present invention relates to agents capable of binding to CLEVER-1 for use in immunostimulation and methods based thereto.
本発明の背景を説明するために本明細書中において使用される刊行物およびその他の文献、およびとりわけ実施に関する追加的な詳細を提供するケースは、参考文献として組み込まれる。 Publications and other publications used herein to illustrate the background of the invention, and in particular cases that provide additional details regarding practice, are incorporated as references.
CLAVER-1は、特許文献1に開示されるタンパク質、共通リンパ管内皮および血管内皮受容体-1であり、スタビリン-1またはFeel-1としても知られる。CLEVER-1は、非特許文献1にも概説されている。CLEVER-1は、リンパ管内皮細胞、ある血管内皮細胞において発現されるが、マクロファージの亜集団においても発現される。CLEVER-1は、2型マクロファージの亜群およびヒト単球に対する除去(scavenging)能力を与える多機能分子である。
CLAVER-1 is a protein, common lymphatic endothelial and vascular endothelial receptor-1 disclosed in
マクロファージは、腫瘍の増殖または退行において重要な役割を果たす。腫瘍随伴マクロファージ(TAMs)の機序は、例えば、非特許文献2に開示されている。M2マクロファージは、ヒトがんにおいて優勢であり、腫瘍の増殖を刺激するが、これらの腫瘍促進マクロファージは、がん増殖を遅くさせるまたは停止させることを目指して腫瘍増殖阻害マクロファージ(M1マクロファージあるいは炎症性マクロファージとも呼ばれる)へと変化させることができる。したがって、マクロファージ亜型(phenotype)の変化は、種々のがんの免疫療法における有望なアプローチである。しかしながら、TAMsを標的とすることを目指す最近利用可能となった治療薬でがんを治療する試みは、望まない副作用を伴い、例えば、マクロファージ治療アプローチはすべてのマクロファージを標的とするため、全身毒性を示すかまたは逆説的に腫瘍増殖を促進する。 Macrophages play an important role in tumor growth or regression. The mechanism of tumor-associated macrophages (TAMs) is disclosed, for example, in Non-Patent Document 2. M2 macrophages predominate in human cancer and stimulate tumor growth, whereas these tumor-promoting macrophages aim to slow or stop cancer growth (M1 macrophages or inflammatory). It can be transformed into macrophages). Therefore, changes in macrophage subtypes (phenotypes) are a promising approach in immunotherapy for various cancers. However, attempts to treat cancer with recently available therapeutic agents aimed at targeting TAMs have unwanted side effects, such as systemic toxicity because the macrophage treatment approach targets all macrophages. Or paradoxically promote tumor growth.
ヒトCLEVER-1に結合することのできる薬剤は、マクロファージを活性化し、それらの亜型をM2マクロファージからM1マクロファージへ切り替えるために使用できることを見出した。特に、TAMs上のCLEVER-1に結合することのできる、抗体およびその断片、ペプチドまたはマクロ分子などの薬剤は、腫瘍促進マクロファージ(M2)の炎症性マクロファージ(M1)への変化を成し遂げるために使用することができる。本発明は、マクロファージの亜型を切り替えるマクロファージの能力を利用する方法に関する。 It has been found that agents capable of binding to human CLEVER-1 can be used to activate macrophages and switch their subtypes from M2 macrophages to M1 macrophages. In particular, agents such as antibodies and fragments thereof, peptides or macromolecules capable of binding to CLEVER-1 on TAMs are used to achieve the transformation of tumor-promoting macrophages (M2) into inflammatory macrophages (M1). can do. The present invention relates to a method of utilizing the ability of macrophages to switch subtypes of macrophages.
ここで、M2マクロファージのM1マクロファージへの変化は、マクロファージ/単球TNF-アルファ分泌および/またはHLA-DR発現を測定することによりモニターできることを見出した。その結果として、本発明は、患者における抗-CLEVER-1治療の有効性をモニターおよび/または評価する方法を提供する。 Here, it has been found that changes in M2 macrophages to M1 macrophages can be monitored by measuring macrophage / monocyte TNF-alpha secretion and / or HLA-DR expression. As a result, the invention provides a method of monitoring and / or assessing the efficacy of anti-CLEVER-1 treatment in a patient.
本発明は、CLEVER-1に結合することのできる薬剤を患者に投与した後に、M2マクロファージのM1マクロファージへの変化の発生をモニタリングすることによる抗-CLEVER-1治療の有効性の評価方法であって、
(a)上記患者から採取された血液試料から末梢血単球(PBLs)を得る工程、
(b)上記PBLsのTNF-アルファ分泌を測定する工程、および/または
(c)CD14陽性PBLs上のHLA-DR発現を測定する工程、および
(e)工程(b)および(c)で測定されたTNF-アルファ分泌および/またはHLA-DR発現の値を、抗-CLEVER-1治療の有効性を評価するために対照値と比較する工程であって、対照値が、患者においてCLEVER-1に結合することのできる薬剤を投与する前に測定された値、または同じ患者において異なる時点で行われた1つ以上の先の測定値であり、TNF-アルファ分泌またはHLA-DR発現の増加がM2マクロファージのM1マクロファージへの変化を示す工程
を含む方法に関する。
INDUSTRIAL APPLICABILITY The present invention is a method for evaluating the efficacy of anti-CLEVER-1 therapy by monitoring the occurrence of changes of M2 macrophages to M1 macrophages after administering a drug capable of binding to CLEVER-1 to a patient. hand,
(A) A step of obtaining peripheral blood monocytes (PBLs) from a blood sample collected from the above patient,
(B) the step of measuring the TNF-alpha secretion of the PBLs and / or (c) the step of measuring the HLA-DR expression on the CD14-positive PBLs, and (e) the steps (b) and (c). In the step of comparing the value of TNF-alpha secretion and / or HLA-DR expression with the control value to evaluate the efficacy of anti-CLEVER-1 treatment, the control value is changed to CLEVER-1 in the patient. Values measured prior to administration of a drug capable of binding, or one or more previous measurements made at different times in the same patient, with increased TNF-alpha secretion or HLA-DR expression M2. The present invention relates to a method comprising a step of showing a change of macrophages into M1 macrophages.
一実施態様においては、個体においてCLEVER-1に結合することのできる薬剤は、M2マクロファージをM1マクロファージに変化させることにより、腫瘍または抗原免疫抑制の除去において好適である。好ましくは、本発明は、CLEVER-1分子上のエピトープに結合することのできる、抗体またはその断片などの薬剤に関し、該エピトープは、不連続であり、かつヒトCLEVER-1の配列:
PFTVLVPSVSSFSSR(配列番号1)および
QEITVTFNQFTK(配列番号2)
を含む。
In one embodiment, an agent capable of binding CLEVER-1 in an individual is suitable for removing tumor or antigen immunosuppression by transforming M2 macrophages into M1 macrophages. Preferably, the invention relates to an agent such as an antibody or fragment thereof capable of binding to an epitope on the CLEVER-1 molecule, wherein the epitope is discontinuous and the sequence of human CLEVER-1:
PFTVLVPSVSFSSR (SEQ ID NO: 1) and QEITVTFNQFTK (SEQ ID NO: 2)
including.
マクロファージ亜型の変化は、T-細胞活性化を増加させ、最終的には、例えば原発性がん免疫抑制の除去を引き起こす。その結果として、本知見は、個体における免疫系に影響を与える方法を提供し、がんの治療または転移の予防に有用であるが、このアプローチに限定されるものではない。したがって、TAMs上のCLEVER-1に、好ましくはCLEVER-1分子の特定の配列に結合することのできる抗体またはその断片、ペプチドまたはマクロ分子などの薬剤は、個体におけるがんの治療または転移の予防に好適であり、悪性腫瘍周辺の免疫抑制が、M2マクロファージをM1マクロファージに変化させることにより除去される。 Changes in macrophage subtypes increase T-cell activation and ultimately cause, for example, elimination of primary cancer immunosuppression. As a result, the findings provide a method of affecting the immune system in an individual and are useful in the treatment of cancer or prevention of metastasis, but are not limited to this approach. Thus, agents such as antibodies or fragments thereof, peptides or macrophages capable of binding to CLEVER-1 on TAMs, preferably to a particular sequence of the CLEVER-1 molecule, can be used to treat cancer or prevent metastasis in an individual. The immunosuppression around the malignant tumor is removed by changing M2 macrophages to M1 macrophages.
CLEVER-1に、好ましくはCLEVER-1分子の特定の配列に結合することのできる抗体またはその断片、ペプチドまたはマクロ分子などの薬剤は、個体における慢性
感染症の治療に好適であり、感染性抗原に対する免疫抑制が、M2マクロファージをM1マクロファージに変化させることにより除去される。
Drugs such as antibodies or fragments thereof, peptides or macrophages capable of binding to CLEVER-1, preferably to a particular sequence of the CLEVER-1 molecule, are suitable for the treatment of chronic infectious diseases in individuals and are infectious antigens. Immune suppression against is eliminated by transforming M2 macrophages into M1 macrophages.
したがって、抗-CLEVER-1治療の有効性を評価するための本発明の方法は、特に、CLEVER-1に結合することのできる薬剤が、がんの治療または転移の予防、または慢性感染症の治療における使用のために患者に投与される場合に適用することができる。 Therefore, the methods of the invention for assessing the efficacy of anti-CLEVER-1 treatment are such that, in particular, agents capable of binding CLEVER-1 can treat cancer or prevent metastasis, or in chronic infections. It can be applied when administered to a patient for use in treatment.
さらに、CLEVER-1に、好ましくはCLEVER-1分子の特定の配列に結合することのできる薬剤は、ワクチンのアジュバントとしても好適であり、ワクチン抗原に対する免疫抑制が、M2マクロファージをM1マクロファージに変化させることにより除去される。 Furthermore, agents capable of binding to CLEVER-1, preferably to a specific sequence of the CLEVER-1 molecule, are also suitable as vaccine adjuvants, and immunosuppression against vaccine antigens transforms M2 macrophages into M1 macrophages. It is removed by.
もう1つの実施態様において、本発明は、それを必要とする対象に、本願に開示されるCLEVER-1に、好ましくはCLEVER-1分子の特定の配列に結合することのできる薬剤を投与することを含むM2マクロファージをM1マクロファージに変化させる方法に関する。さらに、本発明は、個体におけるがんの治療または転移の予防、または個体における慢性感染症の治療における、そのM2マクロファージをM1マクロファージに変化させる方法の使用に関する。 In another embodiment, the invention administers to a subject in need thereof an agent capable of binding to CLEVER-1 disclosed herein, preferably a particular sequence of the CLEVER-1 molecule. The present invention relates to a method for converting M2 macrophages containing M1 macrophages into M1 macrophages. Furthermore, the present invention relates to the use of a method of converting its M2 macrophages into M1 macrophages in the treatment of cancer or prevention of metastasis in an individual, or in the treatment of chronic infections in an individual.
本発明の定義と詳細な説明
用語「CLEVER-1」は、特許文献1に開示されたタンパク質、共通リンパ内皮および血管内皮受容体-1を示すために使用される。
Definition and Detailed Description of the Invention The term "CLEVER-1" is used to indicate the protein, common lymphatic endothelial and vascular endothelial receptor-1 disclosed in
用語「ヒトCLEVER-1に結合することのできる薬剤」は、抗体およびその断片、またはペプチドなどであって、ヒトCLEVER-1に結合することのできる薬剤を意味する。その薬剤はまた、本願において定義されるヒトCLEVER-1の特定のエピトープに結合する十分な親和性を有するあらゆる他のマクロ分子であってもよい。 The term "drug capable of binding to human CLEVER-1" means an antibody and a fragment thereof, a peptide or the like, which is a drug capable of binding to human CLEVER-1. The agent may also be any other macromolecule with sufficient affinity to bind to a particular epitope of human CLEVER-1 as defined herein.
用語「抗体またはその断片」は、個体においてCLEVER-1分子を結合する能力がある抗体またはその断片を包含する最も広い意味で使用される。特に、キメラ、ヒト化または霊長類化抗体、ならびに抗体断片および一本鎖抗体(例えばFab、Fv)を、それらが所望の生物学的な活性を発揮するかぎり、含むことが理解されるべきである。 The term "antibody or fragment thereof" is used in the broadest sense to include an antibody or fragment thereof capable of binding a CLEVER-1 molecule in an individual. In particular, it should be understood that chimeric, humanized or primated antibodies, as well as antibody fragments and single chain antibodies (eg Fab, Fv), are included as long as they exert the desired biological activity. be.
特に好ましいCLEVER-1アンタゴニストモノクローナル抗体3-266(DSM ACC2519)および3-372(DSM ACC2520)は、両方とも、2001年8月21日に特許手続上の微生物の寄託の国際承認に関するブタペスト条約のもとDSMZ-ドイチェ・ザンルング・フォン・ミクロオルガニズメン・ウント・ツェルクルツレン・ゲーエムベーハー、デー-38124 ブラウンシュヴァイク マシェロデル ヴェク 1ベー(Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH, Mascheroder Weg 1b, D-38124 Braunschweig)に寄託されており、特許文献1に開示されている。 Particularly preferred CLEVER-1 antagonist monoclonal antibodies 3-266 (DSM ACC2519) and 3-372 (DSM ACC2520) are both also part of the Butapest Convention on International Approval of Deposit of Microorganisms for Patent Procedure on August 21, 2001. And DSMZ-Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH, Mascheroder Weg 1b, D-38124 Braunsch It has been deposited in Patent Document 1 and disclosed in Patent Document 1.
用語「患者」または「個体」は、ヒトを意味する。 The term "patient" or "individual" means human.
用語「治療(treatment)」または「治療すること(treating)」は、疾患の完全な治癒のみならず該疾患の改善または軽減を含むものと理解されるべきである。用語「予防(prevention)」は、完全な予防(prevention)、予防(prophylaxis)、ならびに個体の該疾患または障害により罹患するリスクの低下を含むものと理解されるべきである。 The term "treatment" or "treating" should be understood to include not only complete cure of the disease but also amelioration or alleviation of the disease. The term "prevention" should be understood to include complete prevention, prophylaxis, and a reduced risk of suffering from the disease or disorder of an individual.
マクロファージは、2つの異なる亜型:M1およびM2マクロファージに分けることができる。M1マクロファージは、古典的な炎症性マクロファージであり、大量の炎症性サイトカインおよび共刺激分子を産生し、T-細胞応答の活性化に非常に効率的である。M2マクロファージは、対照的に、免疫抑制細胞であり、抗炎症性サイトカインを合成し、制御性T-細胞を誘導し、したがって、抗原誘導T細胞活性化を大いに弱める。腫瘍随伴マクロファージ(TAMs)は、腫瘍環境内でそれらがM2マクロファージ(腫瘍促進マクロファージ)に成熟し、抗腫瘍免疫応答を抑制し、がん増殖における重要な段階である脈管新生スイッチを媒介することから有害であるとみなされている。M2マクロファージは、M1マクロファージ(炎症性マクロファージ)に変化させることができ、そのようなM2からM1への亜型の変換は、腫瘍拒絶を直接または間接に引き起こし得る。 Macrophages can be divided into two different subtypes: M1 and M2 macrophages. M1 macrophages are classical inflammatory macrophages that produce large amounts of inflammatory cytokines and costimulatory molecules and are highly efficient in activating T-cell responses. M2 macrophages, in contrast, are immunosuppressive cells that synthesize anti-inflammatory cytokines and induce regulatory T-cells, thus significantly weakening antigen-induced T cell activation. Tumor-associated macrophages (TAMs) mature into M2 macrophages (tumor-promoting macrophages) in the tumor environment, suppress the antitumor immune response, and mediate the vasculogenesis switch, an important step in cancer growth. Is considered harmful. M2 macrophages can be transformed into M1 macrophages (inflammatory macrophages), and such conversion of the M2 to M1 subtype can directly or indirectly cause tumor rejection.
本文脈において、表現「M1マクロファージ」または「炎症性マクロファージ」は、マクロファージ/単球TNF-アルファ(TNF-α)分泌またはHLA-DR発現の測定レベルの増加により特徴付けられるマクロファージをいう。M2マクロファージのM1マクロファージへの変化は、患者にヒトCLEVER-1に結合することのできる薬剤を投与前に測定された対照値、または同じ患者において異なる時点で行われた1つ以上の先の測定の値と比較して、単球TNF-アルファ分泌およびHLA-DR発現も増加させるであろう。これらのマーカーのレベルは、個体によって異なり、例えばインターフェロン-ガンマなどのサイトカインやLPS活性化は、M2マクロファージによるTNF-アルファ発現を増加させ得るので、単球TNF-アルファ分泌およびHLA-DR発現の測定値を同じ患者の値と比較することは重要である。 In this context, the expression "M1 macrophage" or "inflammatory macrophage" refers to a macrophage characterized by increased levels of macrophage / monocyte TNF-alpha (TNF-α) secretion or HLA-DR expression. Changes in M2 macrophages to M1 macrophages are control values measured prior to administration of a drug capable of binding human CLEVER-1 to a patient, or one or more previous measurements made at different times in the same patient. Compared to the value of, monocyte TNF-alpha secretion and HLA-DR expression will also be increased. Levels of these markers vary from individual to individual, and measurement of monocyte TNF-alpha secretion and HLA-DR expression, as cytokines such as interferon-gamma and LPS activation can increase TNF-alpha expression by M2 macrophages. It is important to compare the values with those of the same patient.
驚くべきことに、M2マクロファージをヒトCLEVER-1に結合することのできる薬剤に接触させることにより活性化し、M1マクロファージに変化させることができるということ見出した。特に、悪性腫瘍に関連したM2マクロファージは、TAMs上のCLEVER-1に結合することのできる薬剤に接触させることにより、M1マクロファージに変化または再分極させることができるということを見出した。両亜型は、同時に存在し、その亜型の両方が腫瘍中に見ることができる。 Surprisingly, they have found that M2 macrophages can be activated and transformed into M1 macrophages by contacting them with agents capable of binding to human CLEVER-1. In particular, it has been found that M2 macrophages associated with malignant tumors can be altered or repolarized into M1 macrophages by contact with agents capable of binding CLEVER-1 on TAMs. Both subtypes are present at the same time and both of the subtypes can be seen in the tumor.
抗原またはそのフラグメント、ペプチドまたはマクロ分子などの薬剤は、上記マクロファージ亜型の変化または再分極を達成するためにヒトCLEVER-1に結合される。CLEVER-1タンパク質に特異的な抗体などの薬剤は、特定のCLEVER-1エピトープを認識することが同定された。結果として、薬剤は、マクロファージの亜型の変化を達成するために、好ましくはCLEVER-1分子上の特異的配列、例えばエピトープに結合し、該エピトープは不連続であり、かつヒトCLEVER-1のアミノ酸配列:
PFTVLVPSVSSFSSR(配列番号1)および
QEITVTFNQFTK(配列番号2)
を含む。
Agents such as antigens or fragments thereof, peptides or macromolecules are bound to human CLEVER-1 to achieve the alteration or repolarization of the macrophage subtype. Drugs such as antibodies specific for the CLEVER-1 protein have been identified to recognize specific CLEVER-1 epitopes. As a result, the agent preferably binds to a specific sequence on the CLEVER-1 molecule, eg, an epitope, in order to achieve a change in macrophage subtype, the epitope being discontinuous and of human CLEVER-1. Amino acid sequence:
PFTVLVPSVSFSSR (SEQ ID NO: 1) and QEITVTFNQFTK (SEQ ID NO: 2)
including.
本発明のいくつかの実施形態において、不連続エピトープは、さらにヒトCLEVER-1の
ATQTGRVFLQ(配列番号:3)、
DSLRDGRLIYLF(配列番号:4)、
SKGRILTMANQVL(配列番号:5)、および
LCVYQKPGQAFCTCR(配列番号:6)
からなる群より選択される1つ以上の配列を含む。
In some embodiments of the invention, the discontinuous epitope further comprises ATQTGRVFLQ (SEQ ID NO: 3) of human CLEVER-1.
DSLRDGRLIYLF (SEQ ID NO: 4),
SKGRILTMANQVL (SEQ ID NO: 5) and LCVYQKPGQAFCTCR (SEQ ID NO: 6)
Contains one or more sequences selected from the group consisting of.
標的タンパク質ヒトCLEVER-1、すなわちヒトスタビリン-1の一部は、配列番号:7に示されている。CLEVER-1分子上のエピトープ配列番号:1、配列番号:2、配列番号:3、配列番号:4、配列番号:5および配列番号:6は、配列番号:7に示された標的タンパク質ヒトCLEVER-1のアミノ酸420-434、473-484、390-399、576-587、615-627および313-327に対応する。ヒトCLEVER-1の不連続エピトープマッピングは、フィンランド特許出願第20165335号により詳細に開示されている。 A portion of the target protein human CLEVER-1, i.e., human stabilin-1, is set forth in SEQ ID NO: 7. The epitope SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5 and SEQ ID NO: 6 on the CLEVER-1 molecule are the target proteins shown in SEQ ID NO: 7, human CLEVER. Corresponds to the amino acids 420-434, 473-484, 390-399, 576-587, 615-627 and 313-327 of -1. The discontinuous epitope mapping of human CLEVER-1 is disclosed in detail by Finnish Patent Application No. 20165353.
TAMs上のCLEVER-1の2つ以上の上記エピトープ配列への特異的結合は、マクロファージ亜型の所望の変化を達成するために特定のエピトープを標的とすることができるため、有害な副作用を伴わない新規ながんの治療方法、または転移の予防方法を提供する。結果として、本明細書に記載された知見は、腫瘍促進マクロファージの増加した量を伴うあらゆる種類の悪性腫瘍または個体が免疫抑制の優位性を示す慢性炎症などの他の病状の治療または予防において特に有用である。その結果として、がんの治療方法または転移の予防方法は、上述の、ヒトCLEVER-1に、好ましくはCLEVER-1分子の特定のエピトープに結合することのできる薬剤を個体に投与することを含む。この方法は、腫瘍の大きさを縮小することによる、および/または;個体における腫瘍の増殖を減少することによる;および/またはがん細胞の移動および転移形成を阻害することによるがんの治療または予防を含む。したがって、良性もしくは悪性腫瘍または悪性腫瘍の転移、例えば皮膚がんおよび結腸癌などを治療することができる。また、白血病、リンパ腫および多発性骨髄腫も治療することができる。とりわけ、黒色腫およびリンパ腫が、動物モデルに基づき治療に非常に良好に応答することが期待される。 Specific binding of CLEVER-1 on TAMs to two or more of the above epitope sequences is accompanied by adverse side effects as specific epitopes can be targeted to achieve the desired change in macrophage subtype. It provides a new method of treating cancer or preventing metastasis. As a result, the findings described herein are particularly in the treatment or prevention of malignant tumors of any type with increased amounts of tumor-promoting macrophages or other medical conditions such as chronic inflammation in which an individual exhibits immunosuppressive predominance. It is useful. As a result, methods of treating or preventing metastasis of cancer include administering to an individual a drug capable of binding to a particular epitope of a human CLEVER-1, preferably the CLEVER-1 molecule described above. .. This method involves treating or treating cancer by reducing the size of the tumor and / or by reducing the growth of the tumor in an individual; and / or by inhibiting the migration and metastasis of cancer cells. Including prevention. Therefore, benign or malignant tumors or metastases of malignant tumors, such as skin cancer and colon cancer, can be treated. It can also treat leukemia, lymphoma and multiple myeloma. In particular, melanoma and lymphoma are expected to respond very well to treatment based on animal models.
マクロファージの亜型を変化させる方法は、線維肉腫、脂肪肉腫、軟骨肉腫、骨肉腫、血管肉腫、リンパ管肉腫、平滑筋肉腫および横紋筋肉腫などのすべての種類の肉腫、中皮腫、髄膜腫、白血病、リンパ腫、ならびに扁平上皮癌、基底細胞癌、腺癌、乳糖癌、嚢胞腺癌、気管支癌、黒色腫、腎細胞癌、肝細胞癌、移行上皮癌、絨毛腫、セミノーマおよび胎生期癌などのすべての種類の癌腫の治療または予防に有用であると考えられる。 Methods for altering macrophage subtypes include all types of sarcomas, mess, and spinal cord, including fibrosarcoma, liposarcoma, chondrosarcoma, osteosarcoma, hemangiosarcoma, lymphangicystoma, smooth myoma, and rhabdomyomyoma. Membranous carcinoma, leukemia, lymphoma, and squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, lactose carcinoma, cystic adenocarcinoma, bronchial carcinoma, melanoma, renal cell carcinoma, hepatocellular carcinoma, transitional epithelial carcinoma, chorionic villi, seminoma and embryo. It may be useful in the treatment or prevention of all types of carcinoma, including stage cancer.
マクロファージはまた、腫瘍の増殖または退行に影響を及ぼす以外に、炎症および感染の消散のあいだに重要な役割を有する。感染において、M1からM2マクロファージへの切り替えが起こり、エフェクター免疫を無効にする抑制環境の発生につながる。その結果として、マクロファージの亜型を変化させる本明細書に記載される知見は、感染性抗原に対する免疫抑制の除去のため慢性感染症の治療においても有用である。上記CLEVER-1に、好ましくはCLEVER-1分子上の2つ以上の特異的エピトープ配列に結合することのできる薬剤を個体に投与することを含む慢性感染症を治療する方法において、該薬剤はM2からM1にマクロファージの亜型を切り替えるためにそれらを活性化し得る。 Macrophages also play an important role during inflammation and infection resolution, in addition to affecting tumor growth or regression. In infection, switching from M1 to M2 macrophages occurs, leading to the development of a suppressive environment that nullifies effector immunity. As a result, the findings described herein that alter macrophage subtypes are also useful in the treatment of chronic infections due to the elimination of immunosuppression against infectious antigens. In a method of treating a chronic infection comprising administering to an individual an agent capable of binding to CLEVER-1 preferably to two or more specific epitope sequences on the CLEVER-1 molecule, the agent is M2. They can be activated to switch macrophage subtypes from to M1.
さらに、個体におけるマクロファージおよび単球上のCLEVER-1に結合することのできる薬剤は、ワクチンのアジュバントとして使用することができる。該薬剤は、マクロファージの再分極を実現し、したがって、ワクチン抗原に対する免疫抑制を除去または少なくとも減少させる。任意の抗原誘導性ワクチン接種は、宿主またはワクチン接種部位が、免疫抑制性エレメントから一時的に外され得る場合に有益である。 In addition, agents capable of binding macrophages and CLEVER-1 on monocytes in individuals can be used as vaccine adjuvants. The agent achieves macrophage repolarization and thus eliminates or at least reduces immunosuppression against vaccine antigens. Any antigen-induced vaccination is beneficial when the host or vaccination site can be temporarily removed from the immunosuppressive element.
CLEVER-1に結合することのできる薬剤および適切な賦形剤を含む医薬組成物は、がんの治療または予防、または慢性感染症の治療における使用に好適である。本発明において用いられる医薬組成物は、意図する目的を達成する任意の手段により投与することができる。例えば、投与は、静脈内、関節内、腫瘍内または皮下ですることができる。薬理学的な活性化合物に加え、化合物の医薬製剤は、好ましくは、活性化合物の薬学的に使用することのできる製剤への加工を容易にする賦形剤および助剤を含む適切な薬学的に許容され得る担体を含む。 Pharmaceutical compositions containing agents capable of binding CLEVER-1 and suitable excipients are suitable for use in the treatment or prevention of cancer or in the treatment of chronic infections. The pharmaceutical composition used in the present invention can be administered by any means to achieve the intended purpose. For example, administration can be intravenous, intra-articular, intratumoral or subcutaneous. In addition to the pharmacologically active compound, the pharmaceutical formulation of the compound is preferably suitable pharmaceuticalally comprising excipients and auxiliaries that facilitate the processing of the active compound into a pharmaceutically usable formulation. Contains acceptable carriers.
M2マクロファージのM1マクロファージへの変化は、ヒト血液試料から単球TNF-アルファ分泌を測定することにより検証することができる。結果として、TNF-アルファの分泌の増加は、個体における治療応答のモニタリングのためのマーカーとして使用することができる。TNF-アルファ分泌は、患者から採取した血液から富化された末梢血単球から測定され得る。測定されたTNF-アルファのレベルは、CLEVER-1に結合することのできる薬剤を患者に投与することを含む治療への患者の応答に対するマーカーとして使用することができ、そのレベルは、該薬剤を患者に投与する前に同じ患者から測定された対照レベルと、または同じ患者における異なる時点で行われた1つ以上の先の測定値と比較される。 Changes in M2 macrophages to M1 macrophages can be verified by measuring monocyte TNF-alpha secretion from human blood samples. As a result, increased TNF-alpha secretion can be used as a marker for monitoring therapeutic response in an individual. TNF-alpha secretion can be measured from peripheral blood monocytes enriched from blood taken from a patient. The measured TNF-alpha level can be used as a marker for the patient's response to treatment, including the administration of a drug capable of binding CLEVER-1 to the patient, the level of which the drug is used. It is compared to a control level measured from the same patient prior to administration to the patient, or to one or more previous measurements made at different time points in the same patient.
M2マクロファージのM1マクロファージへの変化の発生をモニタリングすることによる抗-CLEVER-1療法の有効性の評価方法は、CLEVER-1に、好ましくはCLEVER-1上の2つ以上の特異的エピトープ配列に結合することのできる薬剤が患者に投与された場合、
(a)該患者から採取した血液試料から末梢血単球(PBLs)を得る工程、
(b)該PBLsのTNF-α分泌を測定する工程、および/または
(c)CD14陽性PBLs上のHLA-DR発現を測定する工程、および
(e)工程(b)および(c)で測定されるTNF-α分泌および/またはHLA-DR発現の値を、抗CLEVER-1治療の有効性を評価するために対照値と比較する工程であって、対照値が、CLEVER-1に結合することのできる薬剤を患者に投与する前に測定された値、または同じ患者における異なる時点で行われた1つ以上の先の測定の値であり、TNF-アルファ分泌またはHLA-DR発現の増加はM2マクロファージのM1マクロファージへの変化を示す工程
を含む。
A method for assessing the efficacy of anti-CLEVER-1 therapy by monitoring the development of changes in M2 macrophages to M1 macrophages is to CLEVER-1, preferably to two or more specific epitope sequences on CLEVER-1. If a drug that can bind is administered to the patient
(A) A step of obtaining peripheral blood monocytes (PBLs) from a blood sample collected from the patient.
(B) Measuring TNF-α secretion of the PBLs and / or (c) Measuring HLA-DR expression on CD14-positive PBLs, and (e) Measured in steps (b) and (c). A step of comparing the value of TNF-α secretion and / or HLA-DR expression with a control value to evaluate the efficacy of anti-CLEVER-1 treatment, wherein the control value binds to CLEVER-1. The value measured prior to administration of the capable drug to the patient, or the value of one or more previous measurements made at different time points in the same patient, where increased TNF-alpha secretion or HLA-DR expression is M2. It comprises a step showing the change of macrophages to M1 macrophages.
患者から採取した血液試料から得られた末梢血単球からのTNF-アルファ分泌の測定は、一般的な公知の方法、例えば、市販のTNF-アルファELISAキットを用いて行うことができる。CD14陽性単球上のHLA-DR発現も、フローサイトメトリーによる公知の方法を用いてモニターすることができる。 Measurement of TNF-alpha secretion from peripheral blood monocytes obtained from a blood sample taken from a patient can be performed using a commonly known method, eg, a commercially available TNF-alpha ELISA kit. HLA-DR expression on CD14-positive monocytes can also be monitored using known methods by flow cytometry.
M2マクロファージのM1マクロファージへの変化の発生は、単球TNF-アルファ分泌の測定レベルを、患者におけるCLEVER-1に結合することのできる薬剤の投与前に特定された対照値または同じ患者における異なる時点で行われた1つ以上の先の測定の値と比較することによりモニターすることができる。例えば、先の測定の結果または対照と比較した単球TNF-アルファ分泌のレベルの減少は、M2マクロファージの高い発現を示すために使用され得、一方、先の測定の結果または対照と比較したTNF-アルファのレベルの増加は、M2マクロファージのより低い発現を伴うM1マクロファージのより多い発現を示すために使用され、抗-CLEVER-1治療の有効性を示すために使用することもできる。TNF-アルファのレベルの増加は、M2マクロファージのより低い発現を伴うM1マクロファージのより多くの発現を示し、言い換えれば、それは該療法に対する応答性を特徴付ける。CLEVER-1に結合することのできる薬剤は、M2マクロファージの少なくとも一部を活性化し、M1マクロファージに再分極し、該薬剤の投与後、両マクロファージ亜型が存在し得るが、M1マクロファージの発現の増加が、該薬剤の投与前の状態と比較して観察され得る。 The occurrence of changes in M2 macrophages to M1 macrophages is a control value identified prior to administration of a drug capable of binding CLEVER-1 in a patient or different time points in the same patient to measure levels of monocyte TNF-alpha secretion. It can be monitored by comparing with the values of one or more previous measurements made in. For example, reduced levels of monocyte TNF-alpha secretion compared to the results of previous measurements or controls can be used to indicate high expression of M2 macrophages, while TNF compared to results of previous measurements or controls. Increased levels of-alpha are used to indicate higher expression of M1 macrophages with lower expression of M2 macrophages and can also be used to demonstrate the efficacy of anti-CLEVER-1 therapy. Increased levels of TNF-alpha show more expression of M1 macrophages with lower expression of M2 macrophages, in other words, it characterizes responsiveness to the therapy. A drug capable of binding to CLEVER-1 activates at least a portion of M2 macrophages and repolarizes them into M1 macrophages, and after administration of the drug, both macrophage subtypes may be present, but in the expression of M1 macrophages. An increase can be observed compared to the pre-administration state of the agent.
本発明の一実施形態によれば、測定されるTNF-アルファ分泌の対照値と比較して少なくとも2倍の増加は、M2マクロファージのM1マクロファージへの変化を示し、したがって治療に対する患者の応答性を示す。 According to one embodiment of the invention, an increase of at least 2-fold compared to the measured TNF-alpha secretion control value indicates a change of M2 macrophages to M1 macrophages and thus the patient's responsiveness to treatment. show.
本発明は、以下の非限定的な実施例により説明される。上述の記載に挙げられた実施態様および実施例は、ただ説明の目的のためのものであり、様々な変更や改変が本発明の範囲内で可能であるということが理解されるべきである。 The present invention is described by the following non-limiting examples. It should be understood that the embodiments and examples given above are for illustration purposes only and that various modifications and modifications are possible within the scope of the invention.
実施例1:インビトロでの抗体結合
健常ドナー由来のヒト末梢血単球を集め、それらを約9mlの末梢血からFicoll-グラジエント遠心分離により富化した。その後、それらを低接着96ウェルプレートに、1%ヒトAB血清を補足したIMDM培地中、1.2×106細胞/ウェルの密度で蒔いた。細胞を1μg/mlまたは10μg/mlの抗-CLEVER-1抗体3-372(2001年8月21日にDSMZ-ドイチェ・ザンルング・フォン・ミクロオルガニズメン・ウント・ツェルクルツレン・ゲーエムベーハーに寄託されたDSM ACC2520)またはVH3/VK5(上記特定のCLEVER-エピトープを認識するヒト化抗-CLEVER-1抗体、その抗体の詳細は以下に示す。)で48時間処理した。HLA-DR発現は、48時間後、CD14陽性細胞からLSR Fortessaフローサイトメトリーを用いて測定した。死んだ細胞は、7-AAD細胞生存染色に関する陽性シグナルに基づき解析から除外した。
Example 1: In vitro antibody binding Human peripheral blood monocytes from healthy donors were collected and enriched by Ficoll-gradient centrifugation from approximately 9 ml of peripheral blood. They were then sown in low-adhesion 96-well plates at a density of 1.2 × 106 cells / well in IMDM medium supplemented with 1% human AB serum. Cells were deposited with 1 μg / ml or 10 μg / ml anti-CLEVER-1 antibody 3-372 (DSMZ-Deutsche Zanrun von Microorganizmen und Zellkurtzlen Geembeher on August 21, 2001). It was treated with DSM ACC2520) or VH3 / VK5 (humanized anti-CLEVER-1 antibody recognizing the above-mentioned specific CLEVER-epitope, details of the antibody are shown below) for 48 hours. HLA-DR expression was measured 48 hours later from CD14 positive cells using LSR Fortessa flow cytometry. Dead cells were excluded from analysis based on positive signals for 7-AAD cell survival staining.
ヒトIgGsを参照として用いた。 Human IgGs were used as a reference.
図1Aは、CD14陽性細胞からのHLA-DR発現の測定の結果を示す。CD14陽性細胞におけるHLA-DR発現は、ヒト化抗-CLEVER-1抗体VH3/VK5の処置により、ヒトIgGsの参照と比較して増加した。 FIG. 1A shows the results of measurement of HLA-DR expression from CD14 positive cells. HLA-DR expression in CD14-positive cells was increased by treatment with humanized anti-CLEVER-1 antibody VH3 / VK5 compared to human IgGs references.
処置間の細胞生存率における差異は観察されなかった。したがって、CLEVER-1標的化抗体は単球の生存に影響を与えないと結論付けることができる。 No difference in cell viability between treatments was observed. Therefore, it can be concluded that the CLEVER-1 targeted antibody does not affect monocyte survival.
ヒト化抗-CLEVER-1抗体VH3/VK5
ヒト化抗-CLEVER-1抗体VH3/VK5は、3-372マウスモノクローナル抗体(2001年8月21日にDSMZ-ドイチェ・ザンルング・フォン・ミクロオルガニズメン・ウント・ツェルクルツレン・ゲーエムベーハーに寄託されたDSM ACC2520)から、フィンランド特許出願第20165335号により詳細に開示されているComposite Human Antibody(商標)技術を用いて作製された。ヒト化抗-CLEVER-1抗体VH3/VK5は、本願に定義されるヒトCLEVER-1のエピトープ配列を認識する。
Humanized anti-CLEVER-1 antibody VH3 / VK5
The humanized anti-CLEVER-1 antibody VH3 / VK5 was deposited with the 3-372 mouse monoclonal antibody (DSMZ-Deutsche Zanrun von Microorganizmen und Zellkurtzlen Geembeher on August 21, 2001). It was made from DSM ACC2520) using the Complexe Human Antibody ™ technique disclosed in detail in Finnish Patent Application No. 20165353. The humanized anti-CLEVER-1 antibody VH3 / VK5 recognizes the epitope sequence of human CLEVER-1 as defined in the present application.
実施例2:TNF-αの測定
健常ドナー由来のヒト末梢血単球を集め、実施例1に記載したように富化した。赤血球溶解緩衝液で処理した血液3mlからの単球は、6ウェルプレートに一晩接着させ、PBSで一回洗浄し、3日間、10μg/mlの抗-CLEVER-1抗体3-372またはAK-1と共に培養した。
Example 2: Measurement of TNF-α Human peripheral blood monocytes from healthy donors were collected and enriched as described in Example 1. Monocytes from 3 ml of blood treated with erythrocyte lysis buffer were adhered to a 6-well plate overnight, washed once with PBS, and 10 μg / ml anti-CLEVER-1 antibody 3-372 or AK- for 3 days. Cultivated with 1.
可溶性TNF-アルファは、市販のTNF-アルファELISAキット(インビトロゲン)を用いて培養培地から測定した。測定の結果は、図1Bに示す。TNF-アルファ分泌の増加は、非処理試料またはAK-1による対照処理試料と比較して、抗-CLEVER-1抗体で処理した試料により気付く。 Soluble TNF-alpha was measured from the culture medium using a commercially available TNF-alpha ELISA kit (In vitrogen). The measurement results are shown in FIG. 1B. Increased TNF-alpha secretion is noticed by the sample treated with the anti-CLEVER-1 antibody compared to the untreated sample or the control treated sample with AK-1.
実施例3:マウス同系がんモデル
樹立したE0771マウス乳癌を、5mg/kgの抗-CLEVER-1(mStab1)または同位体対照で3~4日毎に腫瘍が1mm3の大きさに達するまで処置した。フローサイトメトリーを用いて、TAMs、別の単球亜群、および腫瘍浸潤白血球の補充および亜型に対する抗-CLEVER-1処置の効果を評価した。
Example 3: Mouse Syngeneic Cancer Model Established E0771 mouse breast cancer was treated with 5 mg / kg anti-CLEVER-1 (mStab1) or isotope control every 3-4 days until the tumor reached a size of 1 mm3. Flow cytometry was used to evaluate the effect of anti-CLEVER-1 treatment on TAMs, another monocyte subgroup, and tumor infiltrating leukocyte replacement and subtypes.
図2Aは、CLEVER-1に結合する抗体の投与後の同系E0771乳がんにおけるTAM再分極を示す。抗-CLEVER-1で処置した腫瘍は、対照処置腫瘍と比較して同様のレベルのTAMs(CD11b+F4/80+)を示した。しかしながら、抗-CLEVER-1腫瘍におけるTAMs集団は、II型マーカー、CD206の低い発現を有するより炎症性のマクロファージ(Ly6CloMHCIIhi)から構成される FIG. 2A shows TAM repolarization in syngeneic E0771 breast cancer after administration of an antibody that binds to CLEVER-1. Tumors treated with anti-CLEVER-1 showed similar levels of TAMs (CD11b + F4 / 80 + ) compared to control treated tumors. However, the TAMs population in anti-CLEVER-1 tumors is composed of the more inflammatory macrophages (Ly6C lo MHCII hi ) with low expression of the type II marker, CD206.
抗-CLEVER-1処置TAMsは、図2Bに示すように、IgG処置TAMsと比較して有意に多くのTNF-アルファを分泌した。これと一致して、FoxP3+腫瘍浸潤白血球における減少も観察された。 Anti-CLEVER-1 treated TAMs secreted significantly more TNF-alpha compared to IgG treated TAMs, as shown in FIG. 2B. Consistent with this, a decrease in FoxP3 + tumor-infiltrating leukocytes was also observed.
結果は、CLEVER-1が、マクロファージを標的とした免疫療法のための将来性のある標的であること、および抗-CLEVER-1治療の有効性が単球TNF-α分泌によりモニターできるということを示している。 The results show that CLEVER-1 is a promising target for macrophage-targeted immunotherapy, and that the efficacy of anti-CLEVER-1 treatment can be monitored by monocyte TNF-α secretion. Shows.
Claims (2)
(a)ヒト末梢血単球(PBLs)を提供する工程、
(b)前記PBLsをヒト共通リンパ管内皮および血管内皮受容体-1(CLEVER-1)のエピトープに結合することのできるヒト化抗-CLEVER-1抗体またはその断片で処理する工程;
(c)前記PBLsのTNF-アルファ分泌を測定する工程、およびCD14陽性PBLs上のHLA-DR発現を測定する工程、ならびに
(d)工程(c)で測定されたTNF-アルファ分泌およびHLA-DR発現の値を対照値と比較する工程であって、対照値が、ヒト抗CLEVER-1抗体またはその断片で処理する前に測定された値、または異なる時点で行われた1つ以上の先の測定値であり、TNF-アルファ分泌またはHLA-DR発現の増加がM2マクロファージのM1マクロファージへの変化を示し、それが抗-CLEVER-1抗体の有効性を示すことにつながる工程
を含み、
前記エピトープがヒトCLEVER-1の配列:
PFTVLVPSVSSFSSR(配列番号1)、
QEITVTFNQFTK(配列番号2)、
ATQTGRVFLQ(配列番号:3)、
DSLRDGRLIYLF(配列番号:4)、
SKGRILTMANQVL(配列番号:5)、および
LCVYQKPGQAFCTCR(配列番号:6)
を含む方法。 A method for monitoring changes in M2 macrophages to M1 macrophages.
(A) Step of providing human peripheral blood monocytes (PBLs),
(B) Treatment of the PBLs with a humanized anti-CLEVER-1 antibody or fragment thereof capable of binding to an epitope of human common lymphatic endothelial and vascular endothelial receptor-1 (CLEVER-1);
(C) A step of measuring TNF-alpha secretion of the PBLs, a step of measuring HLA-DR expression on CD14-positive PBLs, and (d) a step of measuring TNF-alpha secretion and HLA-DR measured in step (c). In the step of comparing the value of expression to the control value, the control value is the value measured prior to treatment with the human anti-CLEVER-1 antibody or fragment thereof, or one or more of the above performed at different time points. It is a measurement and includes a step in which an increase in TNF-alpha secretion or HLA-DR expression indicates a change in M2 macrophages to M1 macrophages, which leads to the efficacy of anti-CLEVER-1 antibody.
The epitope is the sequence of human CLEVER-1:
PFTVLVPSVSFSSR (SEQ ID NO: 1),
QEITVTFNQFTK (SEQ ID NO: 2),
ATQTGRVFLQ (SEQ ID NO: 3),
DSLRDGRLIYLF (SEQ ID NO: 4),
SKGRILTMANQVL (SEQ ID NO: 5) and LCVYQKPGQAFCTCR (SEQ ID NO: 6)
How to include.
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US20220227858A1 (en) | 2021-01-18 | 2022-07-21 | Faron Pharmaceuticals Oy | Controlling of immune activation by soluble clever-1 |
WO2023105118A1 (en) * | 2021-12-07 | 2023-06-15 | Faron Pharmaceuticals Oy | Method for using inflammatory markers to guide anti-clever-1 cancer treatment |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2005523247A (en) * | 2002-01-09 | 2005-08-04 | ファロン ファーマシュティカルズ オサケ ユキチュア | Common lymphatic endothelium and vascular endothelial receptor-1 (CLEVER-1) and uses thereof |
JP2012524536A (en) * | 2009-04-22 | 2012-10-18 | ファロン ファーマシューティカルズ オサケ ユキチュア | Novel cell and method of treatment and diagnosis based on the cell |
WO2014209802A1 (en) * | 2013-06-25 | 2014-12-31 | Vaccinex, Inc. | Use of semaphorin-4d inhibitory molecules in combination with an immune modulating therapy to inhibit tumor growth and metastases |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2014072441A1 (en) | 2012-11-09 | 2014-05-15 | Transgene Sa | Modulation of monocytes, or precursors thereof, differentiation |
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Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2005523247A (en) * | 2002-01-09 | 2005-08-04 | ファロン ファーマシュティカルズ オサケ ユキチュア | Common lymphatic endothelium and vascular endothelial receptor-1 (CLEVER-1) and uses thereof |
JP2012524536A (en) * | 2009-04-22 | 2012-10-18 | ファロン ファーマシューティカルズ オサケ ユキチュア | Novel cell and method of treatment and diagnosis based on the cell |
WO2014209802A1 (en) * | 2013-06-25 | 2014-12-31 | Vaccinex, Inc. | Use of semaphorin-4d inhibitory molecules in combination with an immune modulating therapy to inhibit tumor growth and metastases |
Non-Patent Citations (3)
Title |
---|
KUNG, A. L.: "Practices and pitfalls of mouse cancer models in drug discovery", ADV CANCER RES, vol. 96, JPN6021038860, 2006, pages 191 - 212, ISSN: 0005022781 * |
PALANI, S. ET AL.: "Monocyte stabilin-1 suppresses the activation of Th1 lymphocytes", J IMMUNOL, vol. 196, no. 1, JPN6020048518, 1 January 2016 (2016-01-01), pages 115 - 123, XP055706096, ISSN: 0005022779, DOI: 10.4049/jimmunol.1500257 * |
三重元弥, 外: "がん免疫療法の評価動物モデルの現状と課題", 日薬理誌, vol. 148, JPN6021038859, 2016, pages 144 - 148, ISSN: 0005022780 * |
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JP7100588B2 (en) | 2022-07-13 |
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JP2019521312A (en) | 2019-07-25 |
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KR20180133854A (en) | 2018-12-17 |
BR112018070350A2 (en) | 2019-01-29 |
US10884000B2 (en) | 2021-01-05 |
WO2017182706A1 (en) | 2017-10-26 |
CN109153720A (en) | 2019-01-04 |
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